For all the progress the field of neuroscience has made in tracking down the underlying pathology of neurodegenerative diseases, the brain remains a largely unexplored organ, composed of numerous "black box" modules that process information and lengthy tracts that, like cables, convey that processed information to distant regions, either igniting or suppressing further brain activity depending on the message being carried. Trying to untangle this circuitry is like trying to untangle the mass of wires coming out of the power strip behind your bed. Everything could, in principle, be connected to anything.

Now, the marriage of two sophisticated brain-research technologies has spawned a clearer understanding of the brain circuitry whose faltering function underlies Parkinson's disease. In a study published in Neuron, Stanford neuroscientist and bioengineer Jin Hyung Lee, PhD, and her colleagues obtained not just a higher-resolution map of two key brain circuits long understood to play starring roles in the disorder, but a readout of the actual - as opposed to theorized - real-time effects, brain-wide, of stimulating one or the other of those circuits.

With well over 50 million people worldwide living with Parkinson's disease, the study's findings bode well for further improvements in an increasingly widely used approach providing symptomatic relief from the condition.

Parkinson's arises when - for reasons that remain mysterious - nerve cells bundled into a tract running from deep in the brain to a midbrain structure called the striatum begin to die off. These nerve cells secrete a chemical called dopamine. Within the striatum are yet other nerve cells that have receptors for dopamine and from which snake two lengthy, complicated chains of serially connected nerve cells relaying signals far and wide throughout the brain.

These two chains, the so-called "direct" and "indirect" dopamine pathways, work in different ways on different downstream brain structures. But the net effect of their response to dopamine is to induce or impede activity in several distinct downstream brain structures, in the aggregate enhancing voluntary movement.

In the study, Lee's team simultaneously employed optogenetics, which employs laser light to stimulate specific cells that have selectively been rendered sensitive to certain wavelengths of light, with whole-brain functional magnetic resonance imaging, which detects activity in nerve-cell clusters and tracts throughout the brain. That allowed the scientists to precisely stimulate specific nerve cells in one or another of the two crucial pathways at will, at a time of their choosing, and observe the immediate effects on widely scattered brain structures.

The result: a highly accurate determination of exactly what happens, where, when specific points in the direct or indirect pathways are stimulated.

Parkinson's visible symptoms - tremor, difficulty in initiating movement, and postural imbalance - symptoms can be vastly ameliorated by carefully targeted deep-brain stimulation ("DBS"), supplied by a device implanted in the chest and hooked to fine electrical filaments that run to specific parts of the brain. More than 100,000 DBS devices have been implanted in Parkinson's patients. While not necessarily slowing the progression of the underlying brain pathology, they've greatly improved many people's quality of life.

"DBS for Parkinson's disease has led to extraordinary symptomatic relief for some patients," says Lee. "However, it doesn't work in all patients. In others it works, but to only varying degrees. And in all cases, as the disease progresses ineluctably, DBS becomes less effective."

A major obstacle, Lee says, has been that the targets for stimulation are chosen by educated guesswork. Her new study points the way to more precise target selection.

The scenario many of us learned in school is that two X chromosomes make someone female, and an X and a Y chromosome make someone male. These are simplistic ways of thinking about what is scientifically very complex.